NFKB2 mutation as a rare cause of disseminated molluscum contagiosum in a child

To the Editor,

The nuclear factor kappa B (NF‐κB) signaling pathway is a key regulator of innate and adaptive immunity, and responsible for governing lymphocyte development, survival, and activation. ¹ NF‐κB comprises canonical and non‐canonical branches, with non‐canonical signaling crucial for B‐cell maturation and humoral immune homeostasis. Disruption of NF‐κB signaling results in diverse primary immunodeficiencies, with NFKB1 and NFKB2 variants representing the most common monogenic defects. ¹ Heterozygous mutations in the NFKB2 gene, which encodes the p100/p52 subunit of the non‐canonical NF‐κB pathway, are associated with predominantly antibody deficiencies and common variable immunodeficiency (CVID)‐like phenotypes, often accompanied by variable autoimmune and endocrine manifestations. ²

The clinical spectrum of NFKB2‐related disease is highly heterogeneous, ranging from recurrent infections to immune dysregulation. Although severe or persistent viral infections—including herpes simplex virus (HSV) and cytomegalovirus (CMV)—have been reported, disseminated molluscum contagiosum has not been described as a presenting feature. ³

Molluscum contagiosum, caused by molluscum contagiosum virus, is a common childhood infection characterized by umbilicated papules and is typically self‐limiting in children who are immunocompetent. ⁴ In contrast, disseminated or treatment‐refractory disease should prompt evaluation for an underlying inborn error of immunity. Here, we present a child with disseminated molluscum contagiosum as the initial manifestation of NFKB2‐associated immunodeficiency with a CVID‐like phenotype.

A 22‐month‐old boy was admitted to our outpatient clinic with widespread skin lesions. His first lesion appeared on the face approximately 6 months before admission and progressively disseminated, involving his face, trunk, and extremities over time. There was no history of recurrent or severe infections before this presentation. His prenatal, natal, and postnatal histories were unremarkable and there was no parental consanguinity or family history of primary immunodeficiency.

Upon physical examination, the patient's height and weight percentiles were within age‐appropriate ranges. There were numerous papular lesions with central umbilication (some covered with crusts) predominantly involving his face, anterior chest, and trunk (Figure 1A). The patient was noted to have normal hair and nail structures, and no clinical findings suggestive of ectodermal dysplasia were identified. Systemic physical examination revealed no abnormal findings other than the cutaneous lesions. Based on these clinical findings, the patient was diagnosed with molluscum contagiosum. The lesions of molluscum contagiosum were widely distributed over the back and trunk, covering approximately 30%–35% of the total body surface area, prompting an evaluation for an underlying immunodeficiency. Laboratory investigations showed no cytopenia on complete blood count. Serum immunoglobulin levels were measured using a turbidimetric method and IgG (461 mg/dL, reference range 605–1430 mg/dL) and IgA (16 mg/dL reference range 30–107 mg/dL) were considerably lower than the reference ranges, while IgM levels were within the normal range (88 mg/dL, reference range 66–228 mg/dL). ⁵ Total IgE level was 1.65 IU/mL (< 2 IU/mL). Peripheral blood lymphocyte subset analysis showed a markedly reduced CD19⁺ B‐cell percentage of 5% with an absolute count of 271 cells/μL (age‐matched reference range 16%–35% and 720–2600 cells/μL, respectively). In contrast, CD3⁺ was 75% (53%–75%) and natural killer (NK) cells (CD16⁺56⁺) were 12% (3%–15%), although at or approaching the upper limit, both parameters remaining within age‐adjusted reference ranges (Table 1). ⁶ Evaluation of vaccine‐specific antibody responses showed no detectable IgG antibodies to varicella and measles. These findings were consistent with predominant humoral immunodeficiency, characterized by a severe reduction in at least two serum immunoglobulin isotypes alongside a normal or decreased number of B cells, which is indicative of a CVID phenotype. We started regular immunoglobulin replacement therapy (IgRT) for the patient every 3 weeks and observed marked regression in cutaneous lesions at 4 months IgRT (Figure 1B shows the patient 1 year after IgRT). The patient remained clinically stable thereafter and without the development of new viral infections. Due to initial laboratory constraints, detailed B‐cell and T‐cell differentiation analyses could be performed at 4 years of age during IgRT, and all parameters were within normal limits. Clinical exome sequencing identified a heterozygous variant in exon 18 of the NFKB2 gene (c.2042C>T, p.Pro681Leu), a change predicted to affect the function of the non‐canonical NF‐κB signaling pathway. The mutation is localized within the ankyrin repeat domain of the protein and according to the American College of Medical Genetics and Genomics variant interpretation guidelines, this variant was classified as a variant of uncertain significance.

FIGURE 1.

(A) Disseminated molluscum contagiosum lesions on the patient's posterior trunk at presentation. (B) After one year of immunoglobulin replacement therapy.

TABLE 1.

Laboratory and immunological findings at presentation and during follow‐up.

Laboratory parameters	At presentation (age: 22 months) value (reference range)	At follow‐up (Age: 4 years) value (reference range)
Lymphocyte count (cells/mm3)	5420 (3600–8900)	3770 (2300–5400)
Neutrophil count (cells/mm3)	2950 (>1500)	2979 (>1500)
Eosinophil count (cells/μL)	460 (<500)	180 (<500)
Serum IgG (mg/dL)	461 (605–1430)	828 (745–1804)
Serum IgA (mg/dL)	16 (30–107)	44 (57–282)
Serum IgM (mg/dL)	88 (66–228)	78 (78–261)
Total IgE (IU/mL)	1.65 (>2)	4.99 (>2)
Peripheral lymphocyte subsets
CD3+ (%)	75 (53–75)	83 (56–75)
CD4+ (%)	45 (32–51)	50 (28–47)
CD8+ (%)	30 (14–30)	33 (16–30)
CD19+ (%)	5 (16–35)	13 (14–33)
CD16+CD56+ (%)	12 (3–15)	4 (4–17)
CD4+/CD8+ ratio	1.5	1.5
CD19+CD27+ (%)	—	26 (7–24)
CD19+CD27+IgM+IgD+ (%)	—	73 (3–24)
CD19+CD27+IgM−IgD− (%)	—	23 (6–31)
CD4+CD45RA+ (%)	—	41 (54–83)
CD4+CD45RO+ (%)	—	22 (12–42)
CD4+CD45RA+CD31+ (%)	—	52 (47–77)
CD3+ TCR α/β+ (%)	—	90
CD3+ TCR γ/δ+ (%)	—	9

Family segregation analysis highlighted the presence of the same NFKB2 variant in the father. Clinical and immunological evaluation of the father revealed no abnormalities, and no history of recurrent or severe infections, autoimmunity, endocrinopathy, lymphoproliferation, or other manifestations suggestive of NFKB2 deficiency. Also, serum immunoglobulin levels were within the normal reference ranges.

The patient was evaluated for pituitary dysfunction. Endocrinological assessments, including thyroid function tests, insulin like growth factor‐1 (IGF‐1), prolactin, and prepubertal gonadotropin and testosterone levels and adrenocorticotropic hormone (ACTH)—were all within age‐appropriate reference ranges. Given the borderline basal morning cortisol level (6.32 μg/dL), a low‐dose (1 μg) ACTH stimulation test was performed and excluded adrenal insufficiency with serum cortisol increasing from 12.8 μg/dL to a peak of 25.6 μg/dL after stimulation (Δ cortisol: 12.8 μg/dL). Additionally, autoimmune screening, including thyroid autoantibodies and tissue transglutaminase IgA, was unremarkable. As of now, the patient is age 5 years and continues to receive regular IgRT.

Germline NFKB2 mutations impair p100‐to‐p52 processing within the non‐canonical NF‐κB pathway, disrupting BAFF‐R‐mediated, CD40‐mediated, and LTβR‐mediated signaling essential for B‐cell maturation and memory formation, and leading to hypogammaglobulinemia with defective antibody responses. These mutations were initially linked to a CVID‐like phenotype, underscoring the crucial role of non‐canonical NF‐κB signaling in human B‐cell homeostasis. However, subsequent studies showed that, in addition to humoral defects, patients exhibit reduced Th17, circulating T follicular helper cells, and regulatory T‐cell subsets, reflecting broader immune dysregulation. ³ This combined immunological impairment predisposes to weakened mucocutaneous barrier immunity and facilitates viral persistence.

For NFKB2 deficiency, susceptibility to viral skin infections extends beyond antibody defects, as impaired non‐canonical NF‐κB signaling disrupts CD27–CD70 and CD40 pathways that are essential for cytotoxic T‐cell and NK‐cell‐mediated herpesvirus control. Severe mucocutaneous herpes vegetans with viremia has been reported, underscoring the role of cellular immune dysfunction in viral susceptibility. ⁷

Impaired NK cell function has been reported in patients with NFKB2 mutations and can contribute to increased viral susceptibility by compromising the elimination of virus‐infected cells. Defective NK‐cell cytotoxicity was described in a patient with CVID‐like disease caused by an NFKB2 mutation, ⁸ and in severe mucocutaneous herpes infection associated with NFKB2 deficiency. Although NK cell dysfunction can further impair antiviral immunity in NFKB2 deficiency, we were unable to study NK cell function in this patient.

According to Meissner et al., central truncations to the ankyrin repeat domain are associated with a milder clinical phenotype (characterized by attenuated immunodeficiency) and limited autoimmune or endocrinological involvement. Consistent with this genotype–phenotype correlation, our patient exhibited a mild clinical course without autoimmune or endocrinological involvement. ⁹

Immunoglobulin replacement therapy supports antibody‐mediated viral control by providing a broad repertoire of neutralizing IgG antibodies. Additionally, IgRT enhances antiviral immune responses via immunomodulatory effects, including Fc receptor interactions, regulation of the complement system, and modulation of cytokine responses. ¹⁰ In this context, the regression of lesions observed in our patient following IgRT is likely attributable to these immunoregulatory mechanisms.

A limitation of our study is that detailed B‐cell and T‐cell differentiation analyses could not be performed at the time of diagnosis; therefore, switched memory B‐cell levels at presentation could not be established. However, considering the reduced IgG and IgA levels, decreased CD19⁺ B‐cell counts, impaired specific antibody responses, and the presence of a potentially relevant genetic variant in the patient, a CVID‐like phenotype was initially considered. Due to ongoing IgRT, live vaccines could not be administered, and vaccine‐specific antibody responses following recall boosting could not be evaluated. Lastly, a notable limitation of this report involves the inability to screen for anti‐cytokine autoantibodies, particularly anti‐type I interferon antibodies, owing to the limited availability of specialized laboratory assays.

To the best of our knowledge, this is the first case of NFKB2 deficiency presenting with disseminated molluscum contagiosum as the initial manifestation was notably lacking recurrent or severe bacterial infections, autoimmunity, or endocrinopathy. This case suggests that NFKB2‐related immunodeficiency can present with predominant viral cutaneous infections rather than the classical infection pattern.

AUTHOR CONTRIBUTIONS

Ebru Arik Yilmaz: Conceptualization; methodology; writing – review and editing; supervision; visualization; investigation; validation. Cansu Kavukcu Horasan: Investigation; data curation; validation. Mustafa Beykan Istanbullu: Data curation; investigation; validation. Cebbar Yildirimcakar: Writing – original draft; data curation; investigation; conceptualization; visualization; validation.

CONFLICT OF INTEREST STATEMENT

All authors declare no conflicts of interest.

ETHICS STATEMENT

Ethical approval was not required for this single case report according to institutional policy.

CONSENT

Written informed consent was obtained from the parents of the patient.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.